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Background People living with HIV who were diagnosed before highly active antiretroviral therapy became available in 1996 and who survived at least 15 years after HIV diagnosis, termed long-term survivors (LTS), form a particularly vulnerable population. We study social, clinical and mental factors of LTS in the Swiss HIV Cohort Study, with a particular focus on people who inject drugs (PWID).Methods We quantified differences between PWID LTS, and men who have sex with men (MSM) and heterosexual (HET) LTS. Using phylogenetic methods, we distinguished between heterosexual LTS who most likely shared a social network with PWID at the time of infection, termed clusteredHET, and those who did not, termed HET not clustered (HETnc). The analysis was performed using data collected at least 15 years post diagnosis.Results Overall, 1,663 of 5,686 (29.2%) PWID were LTS. We found significant differences between PWID LTS and MSM/HETnc LTS regarding self-reported depression (59.4% versus 43.3%; odds ratio [OR]=1.8; P<0.001), incarceration (30.6% versus 7.0%; OR=6.9; P<0.001) and full work ability (25.4% versus 59.0%; OR=0.27; P<0.001). ClusteredHET were less vulnerable with respect to these variables than PWID LTS but more at risk compared with MSM/HETnc LTS, indicating that clusteredHET are closer to PWID with regard to social and mental aspects compared with all MSM/HETnc.Conclusions Even more than 15 years post HIV diagnosis, special care for HIV-positive PWID is needed, with emphasis on mental health and social integration of PWID LTS.

Background Nucleoside (or nucleotide) reverse transcriptase inhibitors (NRTIs) cause side effects in some patients, prompting the use of either partly or fully NRTI-sparing regimens.Methods We used data from the Swiss HIV Cohort Study to estimate the effectiveness of two new dolutegravir dual regimens relative to the alternative NRTI-sparing dual regimens that our clinicians used previously. We emulated two trials by propensity score matching case patients on the dolutegravir regimen with control patients on an alternative regimen. We analysed the case control sets using a Bayesian Cox model and estimated effectiveness as the percentage still on their trial regimen without virological failure at 48 weeks.Results In a comparison of partly NRTI-sparing regimens, 58 cases treated with dolutegravir were matched to 17 controls treated with boosted darunavir (both with lamivudine or emtricitabine). The estimated difference in effectiveness was 15% (95% credible interval [CrI] 2–33) and 12% (95% CrI 0–26) in two sequential analyses 1 year apart. In a comparison of fully NRTI-sparing regimens, 54 cases treated with dolutegravir were matched to 32 controls treated with raltegravir (both with boosted darunavir). The estimated difference in effectiveness was 9% (95% CrI -1–21) and 5% (95% CrI -4–15) in the two sequential analyses.Conclusions Estimates of relative effectiveness suggest that both dolutegravir regimens are not inferior to these alternative regimens. All four regimens seem suitable for patients needing an NRTI-sparing regimen: there were few virological failures and few treatment changes due to toxicity.

Background Despite being used by more than 18 million people our understanding of the extent of the effects of antiretrovirals on the human body and other organisms remains incomplete. In addition, the direct effect of antiretrovirals on the gut microbiota of HIV-infected individuals has been largely overlooked in microbiome studies concerned with HIV-infected individuals.Methods Here we tested 25 antiretrovirals on Bacillus subtilisand Escherichia coliusing a broth microdilution assay to assess whether these drugs have an antibacterial effect.Results We found that several widely used antiretroviral drugs have in vitroantibacterial activity against both gram-positive and gram-negative commensal bacteria. Efavirenz inhibited the growth of B. subtiliswith a minimum inhibitory concentration (MIC) of 16 µg/ml (in all three replicates), while 2‘,3‘-dideoxyinosine and zidovudine inhibited the growth of E. coliwith an MIC of 16–32 µg/ml and 0.016–0.125 µg/ml (respectively).Conclusions Given the large and increasing number of individuals on antiretrovirals, and the lifelong nature of HIV treatment, this proof-of-concept report could have several potential implications, including an impact of antiretrovirals on bacterial coinfections, as well as potentials for drug discovery and repositioning.

Background Management of persistent low-level viraemia (pLLV) in patients on combined antiretroviral therapy (cART) with previously undetectable HIV viral loads (VLs) is challenging. We examined virological outcome and management among patients enrolled in the Swiss HIV Cohort Study (SHCS).Methods In this retrospective study (2000–2011), pLLV was defined as a VL of 21–400 copies/ml on = three consecutive plasma samples with =8 weeks between first and last analyses, in patients undetectable for =24 weeks on cART. Control patients had = three consecutive undetectable VLs over =32 weeks. Virological failure (VF), analysed in the pLLV patient group, was defined as a VL>400 copies/ml.Results Among 9,972 patients, 179 had pLLV and 5,389 were controls. Compared to controls, pLLV patients were more often on unboosted protease inhibitor (PI)-based (adjusted odds ratio [aOR; 95% CI] 3.2 [1.8, 5.9]) and nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)-only combinations (aOR 2.1 [1.1, 4.2]) than on non-nucleoside reverse transcriptase inhibitor and boosted PI-based regimens. At 48 weeks, 102/155 pLLV patients (66%) still had pLLV, 19/155 (12%) developed VF and 34/155 (22%) had undetectable VLs. Predictors of VF were previous VF (aOR 35 [3.8, 315]), unboosted PI-based (aOR 12.8 [1.7, 96]) or NRTI-only combinations (aOR 115 [6.8, 1,952]), and VLs>200 during pLLV (aOR 3.7 [1.1, 12]). No VF occurred in patients with persistent very LLV (21-49 copies/ml; n=26). At 48 weeks, 29/39 patients (74%) who changed cART had undetectable VLs, compared with 19/74 (26%) without change (P<0.001).Conclusions Among patients with pLLV, VF was predicted by previous VF, cART regimen and VL=200. Most patients who changed cART had undetectable VLs 48 weeks later. These findings support cART modification for pLLV>200 copies/ml.

Background We investigated changes in biomarkers of liver disease in HIV–HCV-coinfected individuals during successful combination antiretroviral therapy (cART) compared to changes in biomarker levels during untreated HIV infection and to HIV-monoinfected individuals.Methods Non-invasive biomarkers of liver disease (hyaluronic acid [HYA], aspartate aminotransferase-to-platelet ratio index [APRI], Fibrosis-4 [FIB-4] index and cytokeratin-18 [CK-18]) were correlated with liver histology in 49 HIV–HCV-coinfected patients. Changes in biomarkers over time were then assessed longitudinally in HIV–HCV-coinfected patients during successful cART (n=58), during untreated HIV-infection (n=59), and in HIV-monoinfected individuals (n=17). The median follow-up time was 3.4 years on cART. All analyses were conducted before starting HCV treatment.Results Non-invasive biomarkers of liver disease correlated significantly with the histological METAVIR stage (P<0.002 for all comparisons). The mean ±sdarea under the receiver operating characteristic (AUROC) curve values for advanced fibrosis (=F3 METAVIR) for HYA, APRI, FIB-4 and CK-18 were 0.86 ±0.05, 0.84 ±0.08, 0.80 ±0.09 and 0.81 ±0.07, respectively. HYA, APRI and CK-18 levels were higher in HIV-HCV-coinfected compared to HIV-monoinfected patients (P<0.01). In the first year on cART, APRI and FIB-4 scores decreased (-35% and -33%, respectively; P=0.1), mainly due to the reversion of HIV-induced thrombocytopaenia, whereas HYA and CK-18 levels remained unchanged. During long-term cART, there were only small changes (<5%) in median biomarker levels. Median biomarker levels changed <3% during untreated HIV-infection. Overall, 3 patients died from end-stage liver disease, and 10 from other causes.Conclusions Biomarkers of liver disease highly correlated with fibrosis in HIV-HCV-coinfected individuals and did not change significantly during successful cART. These findings suggest a slower than expected liver disease progression in many HIV-HCV-coinfected individuals, at least during successful cART.

Objective To assess the impact of antiretroviral therapy optimized by genotypic antiretroviral resistance testing (GRT) on healthcare costs over a 2-year period in patients after antiretroviral treatment failure.Study design Non-randomized, prospective, tertiary care, clinic-based study.Patients One-hundred and forty-two HIV patients enrolled in the ‘ZIEL’ study and the Swiss HIV Cohort Study who experienced virological treatment failure.Methods For all patients GRT was used to optimize the antiretroviral treatment regimen. All healthcare costs during 2 years following GRT were assessed using micro-costing. Costs were separated into ART medication costs and healthcare costs other than ART medication (that is, non-ART medication costs, in-patient costs and ambulatory [out-patient] costs). These cost estimates were then split into four consecutive 6-month periods (period 1–4) and the accumulated cost for each period was calculated. Univariate and multivariate regression modelling techniques for repeated measurements were applied to assess the changes of healthcare costs over time and factors associated with healthcare costs following GRT.Results Overall healthcare costs after GRT decreased over time and were significantly higher in period 1 (32%; 95% confidence interval [CI]: 18–47) compared with period 4. ART medication costs significantly increased by 1,017 (95% CI: 22–2,014) Swiss francs (CHF) from period 1–4, whereas healthcare costs other than ART medication costs decreased substantially by a factor of 3.1 (95% CI: 2.6–3.7) from period 1 to period 4. Factors mostly influencing healthcare costs following GRT were AIDS status, costs being 15% (95% CI: 6–24) higher in patients with AIDS compared with patients without AIDS, and baseline viral load, costs being 12% (95% CI: 6–17) higher in patients with each log increase in plasma RNA.Conclusions Optimized antiretroviral treatment regimens following GRT lead to a reduction of healthcare costs in patients with treatment failure over 2 years. Patients in a worse health state (that is, a positive AIDS status and high baseline viral load) will experience higher overall costs.

Objective A high level of adherence to antiretroviral therapy is required for complete suppression of HIV replication, immunological and clinical effectiveness. We investigated whether cognitive behaviour therapy can improve medication adherence.Design Prospective randomized 1-year trial.Setting Collaboration of HIV university outpatient clinic and psychotherapists in private practice.Participants 60 HIV-infected persons on stable anti-retroviral combination therapy and viral load below 50 copies/ml.Intervention Cognitive behaviour intervention in individual patients, in addition to standard of care.Main outcome measures Feasibility and acceptance of intervention; adherence to therapy assessed using medication event monitoring system (MEMS) and self-report questionnaire; virological failure; psychosocial measures.Results The median number of sessions for cognitive behaviour intervention per patient during the 1-year trial was 11 (range 2–25). At months 10–12, mean adherence to therapy as assessed using MEMS was 92.8% in the intervention and 88.9% in the control group (P=0.2); the proportion of patients with adherence =95% was 70 and 50.0% (P=0.014), respectively. While there was no significant deterioration of adherence during the study in the intervention arm, adherence decreased by 8.7% per year (P=0.006) in the control arm. No differences between the intervention group and standard of care group were found regarding virological outcome. Compared with the control group, participants in the intervention group perceived a significant improvement of their mental health during the study period.Conclusions Cognitive behavioural support in addition to standard of care of HIV-infected persons is feasible in routine practice, and can improve medication adherence and mental health.

Background We assessed whether treatment interruptions induce selection of mutations associated with drug resistance in the Swiss–Spanish Intermittent Treatment Trial (SSITT). Patients had been on HAART without previous failure and had undetectable viraemia for at least 6 months. Their HAART was interrupted for 2 weeks and restarted for 8 weeks. After four of these cycles, treatment was definitively interrupted at week 40.Methods Genotypic resistance testing was performed in 87/97 Swiss patients: in those failing treatment before week 40, at the time of first viral rebound >500 copies/ml off treatment and preceding failure to reach RNA <50 copies/ml after 8 weeks of re-treatment; for patients without virological failure, on the first sample with HIV-1 RNA >1000 copies/ml after week 40.Results Mutations associated with drug resistance were detected in 9/25 (36%) patients with virological failure during the first 40 weeks and in 6/59 (10%) patients after week 40. Overall, drug resistance mutations were detected in 17% of patients, all but two with the 184V/I mutation. Among the 74 patients receiving lamivudine, the M184V/I mutation was detected in 13/74 (17.6%) patients. A wild-type codon at position 184 was detected in previous samples in all b'ut two. The relative risk for virological failure was 2.55-fold higher in patients with the M184V/I mutation than in patients without detectable mutation (P=0.007).Conclusions The M184V/I mutation is frequently selected during repeated treatment interruptions.

Objective To determine whether genotypic resistance testing leads to selection of more potent drug regimens when compared to regimens based on treatment history only.Design Prospective, tertiary care centre-based study. Patients: One-hundred-and-forty-five HIV-infected adults on stable antiretroviral therapy (ART) for >6 months experiencing virological failure.Methods The physicians’ decision-making process when choosing a salvage regimen was prospectively documented: at time of virological failure, on ‘failing ART’, genotyping was performed and a hypothetical ‘clinical expert ART’ based upon patient's drug history was documented. Subsequently, data on resistance mutations, rating by a decision support software and drug history were used to define ‘genotyping ART’. After discussion with the patient, final treatment, ‘new personalized ART’ was chosen and prescribed. To compare the relative potency of the four ART regimens in a standardized manner, a resistance score ranging from 1 (best) to 8 (worst) based on drug ranking by decision support software was attributed to each ART regimen. Virological and immunological outcomes were analysed based on the magnitude of the resistance score.Results Median follow-up was 1.5 years. In all 145 patients, median resistance scores for the stepwise selected ART regimens were: ‘failing ART’: 4.5, ‘clinical expert ART’: 1.8, ‘genotyping ART’: 1.5 and ‘new personalized ART’: 2. The latter was 1.5 in patients who effectively switched to ‘new personalized ART’ (n=89). Lower resistance scores translated into significantly improved virological response after initiation of ‘new personalized ART’. In multivariable analysis, lower resistance scores, lower baseline HIV RNA levels and use of novel antiretroviral drugs were associated with the probability of reducing plasma viraemia to <50 copies/ml. Conclusions: This study suggests that treatment choices including genotype and decision support software were virologically superior to those based on drug history only.

The significance of distinct classes of HIV-1 nucleic acids as correlates of recent HIV-1 replication was assessed in peripheral blood mononuclear cells (PBMC) obtained from 14 patients during 2 weeks of structured interruption of antiretroviral therapy (STI) and 2 weeks of resuming therapy. Levels of HIV RNA in plasma (HIV-RNAplasma) and of unspliced cell-associated HIV-1 RNA (HIV-UsRNAPBMC) were significantly increased as a result of STI, whereas no significant shifts in the levels of 2-LTR episomal HIV-1 DNA (2-LTR circles) and total late HIV-1 reverse transcripts (late-DNA) were observed. Thus, limited viral replication had occurred, which had no effect on the pool size of infected cells in the periphery. Levels of 2-LTR circles did not reflect rapid changes in HIV-1 replication. In contrast, expression of HIV-UsRNAPBMCincreased during STI and consequently provides a more sensitive, albeit not absolute cellular marker of ongoing HIV-1 replication.

Unspliced HIV-RNA (HIV-UsRNA) associated with peripheral blood mononuclear cells (PBMCs) persists in patients on potent antiretroviral therapy even in the absence of detectable plasma HIV-RNA. To further characterize such residual HIV-RNA, cell-associated virion-encapsidated HIV and intracellular unspliced HIV-RNA were differentiated and monitored using a novel highly sensitive method. In addition, expression of HIV-mRNA encoding tatand revwas assessed. PBMCs of patients with unsuppressed plasma viraemia harboured an extracellular fraction of HIV-UsRNA, which correlated highly with intracellular HIV-RNA levels. Thus, extracellular PBMC-associated HIV-RNA may, to a significant extent, reflect nascent virions attached to productively infected cells. Upon treatment with potent antiretroviral therapy resulting in plasma viraemia <50 copies/ml, expression of cell-associated viral particles was hardly discernible in PBMCs but transcription of unspliced HIV-RNA persisted. Given the virtual absence of rev-mRNA, translation of residual HIV-UsRNA was probably precluded by retention of these transcripts in the nucleus. As shown by limiting dilution analysis, HIV-1 infected cells with such a repressed viral transcription pattern were observed at high frequencies in PBMC from untreated patients.